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1.
ASAIO J ; 2024 May 20.
Article in English | MEDLINE | ID: mdl-38776488

ABSTRACT

Patients undergoing veno-arterial extracorporeal membrane oxygenation (VA-ECMO) typically suffer from cardiogenic pulmonary edema and lung atelectasis, which can exacerbate right ventricular (RV) dysfunction through an increase in lung elastance and RV afterload. Invasive mechanical ventilation settings, and positive end-expiratory pressure (PEEP) in particular, can help to improve RV performance by optimizing lung recruitment and minimizing alveolar overdistention. In this report, we present a VA-ECMO supported patient in whom in vivo RV pressure-volume (PV) loops were measured during a decremental PEEP trial, leading to the identification of an optimum PEEP level from a cardio-respiratory viewpoint. This innovative approach of tailoring mechanical ventilation settings according to cardio-respiratory physiology through in vivo RV PV loops may provide a novel way to optimize hemodynamics and patient outcomes.

2.
BMJ Open Qual ; 12(2)2023 05.
Article in English | MEDLINE | ID: mdl-37217240

ABSTRACT

BACKGROUND: Medication administration errors (MAEs) are a major cause of morbidity and mortality. An updated barcode medication administration (BCMA) technology on infusion pumps is implemented in the operating rooms to automate double check at a syringe exchange. OBJECTIVE: The aim of this mixed-methods before-and-after study is to understand the medication administrating process and assess the compliance with double check before and after implementation. METHODS: Reported MAEs from 2019 to October 2021 were analysed and categorised to the three moments of medication administration: (1) bolus induction, (2) infusion pump start-up and (3) changing an empty syringe. Interviews were conducted to understand the medication administration process with functional resonance analysis method (FRAM). Double check was observed in the operating rooms before and after implementation. MAEs up to December 2022 were used for a run chart. RESULTS: Analysis of MAEs showed that 70.9% occurred when changing an empty syringe. 90.0% of MAEs were deemed to be preventable with the use of the new BCMA technology. The FRAM model showed the extent of variation to double check by coworker or BCMA.Observations showed that the double check for pump start-up changed from 70.2% to 78.7% postimplementation (p=0.41). The BCMA double check contribution for pump start-up increased from 15.3% to 45.8% (p=0.0013). The double check for changing an empty syringe increased from 14.3% to 85.0% (p<0.0001) postimplementation. BCMA technology was new for changing an empty syringe and was used in 63.5% of administrations. MAEs for moments 2 and 3 were significantly reduced (p=0.0075) after implementation in the operating rooms and ICU. CONCLUSION: An updated BCMA technology contributes to a higher double check compliance and MAE reduction, especially when changing an empty syringe. BCMA technology has the potential to decrease MAEs if adherence is high enough.


Subject(s)
Medication Errors , Operating Rooms , Humans , Medication Errors/prevention & control , Electronic Data Processing/methods , Medication Systems, Hospital , Infusion Pumps
3.
Front Med (Lausanne) ; 9: 785734, 2022.
Article in English | MEDLINE | ID: mdl-35924039

ABSTRACT

Objective: Adequate oxygenation is essential for the preservation of organ function during cardiac surgery and cardiopulmonary bypass (CPB). Both hypoxia and hyperoxia result in undesired outcomes, and a narrow window for optimal oxygenation exists. Current perioperative monitoring techniques are not always sufficient to monitor adequate oxygenation. The non-invasive COMET® monitor could be a tool to monitor oxygenation by measuring the cutaneous mitochondrial oxygen tension (mitoPO2). This pilot study examines the feasibility of cutaneous mitoPO2 measurements during cardiothoracic procedures. Cutaneous mitoPO2 will be compared to tissue oxygenation (StO2) as measured by near-infrared spectroscopy. Design and Method: This single-center observational study examined 41 cardiac surgery patients requiring CPB. Preoperatively, patients received a 5-aminolevulinic acid plaster on the upper arm to enable mitoPO2 measurements. After induction of anesthesia, both cutaneous mitoPO2 and StO2 were measured throughout the procedure. The patients were observed until discharge for the development of acute kidney insufficiency (AKI). Results: Cutaneous mitoPO2 was successfully measured in all patients and was 63.5 [40.0-74.8] mmHg at the surgery start and decreased significantly (p < 0.01) to 36.4 [18.4-56.0] mmHg by the end of the CPB run. StO2 at the surgery start was 80.5 [76.8-84.3]% and did not change significantly. Cross-clamping of the aorta and the switch to non-pulsatile flow resulted in a median cutaneous mitoPO2 decrease of 7 mmHg (p < 0.01). The cessation of the aortic cross-clamping period resulted in an increase of 4 mmHg (p < 0.01). Totally, four patients developed AKI and had a lower preoperative eGFR of 52 vs. 81 ml/min in the non-AKI group. The AKI group spent 32% of the operation time with a cutaneous mitoPO2 value under 20 mmHg as compared to 8% in the non-AKI group. Conclusion: This pilot study illustrated the feasibility of measuring cutaneous mitoPO2 using the COMET® monitor during cardiothoracic procedures. Moreover, in contrast to StO2, mitoPO2 decreased significantly with the increasing CPB run time. Cutaneous mitoPO2 also significantly decreased during the aortic cross-clamping period and increased upon the release of the clamp, but StO2 did not. This emphasized the sensitivity of cutaneous mitoPO2 to detect circulatory and microvascular changes.

4.
J Radiol Case Rep ; 16(3): 23-32, 2022 Mar.
Article in English | MEDLINE | ID: mdl-35529425

ABSTRACT

Hepatic involvement of sarcoidosis is usually hard to detect on radiological imaging. We present a case of a 60-year-old female with symptoms of pulmonary sarcoidosis. Subsequent imaging work-up showed diffuse hepatic granulomas consistent with abdominal involvement of sarcoidosis. A literature review regarding hepatic sarcoidosis is provided and radiological appearances as well as considerations for differential diagnosis are described.


Subject(s)
Sarcoidosis, Pulmonary , Sarcoidosis , Diagnosis, Differential , Female , Humans , Middle Aged , Radiography , Sarcoidosis/diagnostic imaging , Sarcoidosis/drug therapy , Sarcoidosis, Pulmonary/complications , Sarcoidosis, Pulmonary/diagnostic imaging
5.
Health Syst (Basingstoke) ; 11(1): 68-74, 2022.
Article in English | MEDLINE | ID: mdl-35127060

ABSTRACT

The Thoraxcenter of Erasmus MC started an improvement project in 2015 in order to increase the number of open-heart surgeries by 150 for three consecutive years (450 in total, +46%), and to decrease the access time from 12-14 to 2-3 weeks by the end of 2016. This was required to attain economy of scale in a highly competitive market. In this paper we describe the first year of the project, focusing on its structure and interventions taken, resulting in 165 additional open-heart surgeries carried out in 2016 and a significantly shorter access time of 2-3 weeks.

6.
Br J Anaesth ; 128(4): 636-643, 2022 Apr.
Article in English | MEDLINE | ID: mdl-35031105

ABSTRACT

BACKGROUND: Previous studies have shown that preoperative anaemia in patients undergoing cardiac surgery is associated with adverse outcomes. However, most of these studies were retrospective, had a relatively small sample size, and were from a single centre. The aim of this study was to analyse the relationship between the severity of preoperative anaemia and short- and long-term mortality and morbidity in a large multicentre national cohort of patients undergoing cardiac surgery. METHODS: A nationwide, prospective, multicentre registry (Netherlands Heart Registration) of patients undergoing elective cardiac surgery between January 2013 and January 2019 was used for this observational study. Anaemia was defined according to the WHO criteria, and the main study endpoint was 120-day mortality. The association was investigated using multivariable logistic regression analysis. RESULTS: In total, 35 484 patients were studied, of whom 6802 (19.2%) were anaemic. Preoperative anaemia was associated with an increased risk of 120-day mortality (adjusted odds ratio [aOR] 1.7; 95% confidence interval [CI]: 1.4-1.9; P<0.001). The risk of 120-day mortality increased with anaemia severity (mild anaemia aOR 1.6; 95% CI: 1.3-1.9; P<0.001; and moderate-to-severe anaemia aOR 1.8; 95% CI: 1.4-2.4; P<0.001). Preoperative anaemia was associated with red blood cell transfusion and postoperative morbidity, the causes of which included renal failure, pneumonia, and myocardial infarction. CONCLUSIONS: Preoperative anaemia was associated with mortality and morbidity after cardiac surgery. The risk of adverse outcomes increased with anaemia severity. Preoperative anaemia is a potential target for treatment to improve postoperative outcomes.


Subject(s)
Anemia , Cardiac Surgical Procedures , Anemia/complications , Anemia/epidemiology , Cardiac Surgical Procedures/adverse effects , Humans , Postoperative Complications/epidemiology , Prospective Studies , Registries , Retrospective Studies
7.
J Cardiothorac Vasc Anesth ; 36(4): 1029-1039, 2022 04.
Article in English | MEDLINE | ID: mdl-34518103

ABSTRACT

OBJECTIVES: To determine the impact of a rotational thromboelastometry (ROTEM)-guided transfusion protocol on the use of blood products, patient outcomes, coagulation factor concentrates, and costs. DESIGN: A single-center retrospective cohort study. SETTING: A tertiary university hospital. PATIENTS: Adults undergoing proximal aortic surgery with deep hypothermic circulatory arrest. INTERVENTION: ROTEM-guided transfusion protocol compared with clinically-guided transfusion. MEASUREMENTS AND MAIN RESULTS: Two hundred seventeen patients were included; seventy-one elective and 24 emergency patients in the clinically-guided group, and 59 elective and 63 emergency patients in the ROTEM-guided transfusion protocol group. In the ROTEM-guided transfusion protocol group, a significant reduction in transfusion of red blood cells (5 [3-8] v 2 [0-4], p < 0.001), platelet concentrate (2 [2-3] v 1 [1-2], p < 0.001), and plasma (1,980 mL [1,320-3,300] v 800 mL [0-1,000], p < 0.001) was seen in elective surgery. Emergency patients received fewer red blood cells (7 [5-10] v 5 [2-10], p = 0.040), platelet concentrate (3 [2-4] v 2 [2-3], p = 0.023), and plasma (3,140 mL [1,980-3,960] v 1,000 mL [0-1,400], p < 0.001). Prothrombin complex concentrate and fibrinogen concentrate were increased significantly in elective and emergency patients. The surgical reexploration for bleeding rate was decreased in elective patients 33.8% v 5.1%. CONCLUSION: The implementation of a ROTEM-guided transfusion protocol might have the potential to decrease blood product transfusion and may improve patient outcomes.


Subject(s)
Hematopoietic Stem Cell Transplantation , Thrombelastography , Blood Transfusion/methods , Circulatory Arrest, Deep Hypothermia Induced/adverse effects , Humans , Retrospective Studies , Thrombelastography/methods
8.
Eur Heart J Case Rep ; 5(8): ytab308, 2021 Aug.
Article in English | MEDLINE | ID: mdl-34514303

ABSTRACT

BACKGROUND: Femoral cannulation is commonly used in minimally invasive cardiac surgery to establish extracorporeal circulation. We present a case with a finding that should be evaluated when screening candidates for minimally invasive cardiac surgery. CASE SUMMARY: A 57-year-old male patient was scheduled for minimally invasive repair of the mitral and tricuspid valve and a MAZE procedure. During surgery there was difficulty advancing the venous cannula inserted in the right femoral vein. On transoesophageal echocardiography a guidewire advanced from the femoral vein was observed entering the right atrium from the superior vena cava. Despite inserting a second venous cannula in the jugular vein, venous drainage was insufficient for minimal invasive surgery. The approach was converted to a median sternotomy with bicaval cannulation. Re-examination of the preoperative computed tomography (CT) scan showed an interrupted inferior vena cava (IVC) with azygos continuation. DISCUSSION: In patients with major venous malformations such as the interrupted IVC with azygos continuation a full sternotomy is the preferred approach. The venous system should be evaluated when screening candidates for minimally invasive mitral valve surgery with preoperative CT. Additional cues to suspect interruption of the IVC are polysplenia and a broad superior mediastinal projection on the chest radiograph, mimicking a right paratracheal mass.

9.
Article in English | MEDLINE | ID: mdl-34019749

ABSTRACT

Thoracic surgery is still associated with severe postoperative pain. In this video tutorial, we present 2 techniques that could be used as an additional method in a multimodal postoperative analgesia strategy for video-assisted thoracic surgery. We present the combination of an epipleural surgical infiltration of a local anesthetic with an ultrasound-guided erector spinae plane block.


Subject(s)
Analgesia/methods , Nerve Block/methods , Pain, Postoperative , Thoracic Surgery, Video-Assisted , Ultrasonography, Interventional/methods , Aged , Anesthetics, Local/administration & dosage , Back Muscles/innervation , Combined Modality Therapy , Humans , Male , Pain Management/methods , Pain, Postoperative/etiology , Pain, Postoperative/prevention & control , Pain, Postoperative/therapy , Thoracic Surgery, Video-Assisted/adverse effects , Thoracic Surgery, Video-Assisted/methods , Treatment Outcome
11.
BMJ Open ; 9(11): e031166, 2019 11 02.
Article in English | MEDLINE | ID: mdl-31678946

ABSTRACT

INTRODUCTION: Total knee replacement (TKR) for osteoarthritis results in a satisfactory outcome in the majority of patients, although up to one in five patients may be dissatisfied with the outcome. Persistent pain is a main contributor to patient dissatisfaction, and femoral and tibial component malrotation have been identified as a potential cause for both persistent pain and patellofemoral problems. Based on the assumption that component malrotation is the causative factor for persistent pain, early revision for patients with symptomatic malrotated components has been advocated in the literature. However, convincing evidence that component malrotation indeed results in less than optimal outcomes is lacking. This study aims to assess the relation between knee prosthesis component rotation and patient-reported outcomes in a large group of patients and to determine the range of femoral, tibial and combined rotation that results in the best clinical outcomes. METHODS AND ANALYSIS: In this single-centre, prospective observational cohort study, a total of 500 patients will undergo TKR. All patients will have a 3D-CT assessment of femoral and tibial component rotation within 8 weeks after surgery. Outcome measures will include the Oxford Knee Score, the Knee Injury and Osteoarthritis Outcome Score, EQ-5D, visual analogue scale for pain, the American Knee Society Score and the knee joint range of motion. We will assess the relation between femoral, tibial and combined component rotation and patient-reported outcome measures at 8 weeks and 1 year of follow-up, and we will determine the range of femoral, tibial and combined rotation that results in the best clinical outcomes. ETHICS AND DISSEMINATION: Ethical approval for this study has been granted by the Isala Hospital ethics committee. The results will be published in a peer-reviewed journal and presented at relevant meetings. TRIAL REGISTRATION NUMBER: NL7635.


Subject(s)
Arthralgia/diagnostic imaging , Arthroplasty, Replacement, Knee , Knee Joint/diagnostic imaging , Osteoarthritis, Knee/surgery , Patient Reported Outcome Measures , Postoperative Complications/diagnostic imaging , Prosthesis Failure/adverse effects , Rotation , Arthralgia/physiopathology , Humans , Imaging, Three-Dimensional , Knee Joint/physiopathology , Pain Measurement , Patient Satisfaction , Postoperative Complications/physiopathology , Prospective Studies , Range of Motion, Articular
12.
Interact Cardiovasc Thorac Surg ; 26(5): 820-825, 2018 05 01.
Article in English | MEDLINE | ID: mdl-29309597

ABSTRACT

OBJECTIVES: Reduction of blood loss after cardiac surgery remains challenging. The effectiveness of adherence to a protocol on cessation of anticoagulants and platelet-inhibiting medications was investigated together with the influence of protocol violations on blood loss after surgery, use of blood products, surgical re-explorations and 30-day mortality. METHODS: Between 2009 and 2013, data were collected prospectively for all elective cardiac surgery procedures in adult patients (n = 1637). Two groups were distinguished: Group 1 adhered to the protocol for cessation or continuation of medication (n = 1287, 79%) and Group 2 violated the protocol (n = 350, 21%). RESULTS: Median blood loss was 300 ml (interquartile range 175-500 ml). Eighty patients underwent re-exploration due to blood loss (5%). Thirty-day mortality was 2% (n = 27). Protocol violation was associated with increased blood loss [median 275 ml (175-475 ml) vs 350 ml (250-612); P ≤ 0.001] and with increased average use of fresh frozen plasma (226 ml vs 139 ml; P << 0.00001), red blood cell transfusion (115 ml vs 87 ml; P = 0.081) and thrombocyte transfusions (52 ml vs 37 ml; P = 0.0082). The number of re-explorations (4% vs 6%; P = 0.39) and mortality risk (1% vs 2%; P = 0.72) did not differ. CONCLUSIONS: Balancing the benefit of continuing platelet inhibitors or anticoagulants versus cessation before surgery remains challenging. Adherence to the protocol will lead to lower blood loss and in a lower consumption of blood products although the decision to go for re-exploration and 30-day mortality does not differ compared with the protocol violation. Stopping medication does not lead to thromboembolic events.


Subject(s)
Anticoagulants/therapeutic use , Blood Loss, Surgical/prevention & control , Cardiac Surgical Procedures/adverse effects , Guideline Adherence , Platelet Aggregation Inhibitors/therapeutic use , Postoperative Hemorrhage/prevention & control , Adult , Aged , Blood Transfusion , Cardiac Surgical Procedures/mortality , Clinical Protocols , Elective Surgical Procedures , Female , Humans , Male , Middle Aged , Multivariate Analysis , Postoperative Hemorrhage/etiology , Treatment Outcome
13.
J Radiol Case Rep ; 11(2): 8-15, 2017 Feb.
Article in English | MEDLINE | ID: mdl-28580068

ABSTRACT

Mucoepidermoid carcinoma (MEC) of the airways is a rare entity most often found in young patients. We present a case of a 23 year old patient with symptoms of pneumonia, which progresses to a pulmonary abscess within a week. Diagnostic work-up reveals an endobronchial obstruction by a pedunculated low grade MEC. A literature review is provided and radiological appearances are described.


Subject(s)
Carcinoma, Mucoepidermoid/diagnostic imaging , Lung Abscess/diagnostic imaging , Lung Neoplasms/diagnostic imaging , Pneumonia/diagnostic imaging , Positron Emission Tomography Computed Tomography , Carcinoma, Mucoepidermoid/pathology , Carcinoma, Mucoepidermoid/surgery , Contrast Media , Diagnosis, Differential , Disease Progression , Humans , Lung Abscess/pathology , Lung Abscess/surgery , Lung Neoplasms/pathology , Lung Neoplasms/surgery , Male , Neoplasm Grading , Pneumonia/pathology , Pneumonia/surgery , Young Adult
15.
J Card Surg ; 31(7): 429-31, 2016 Jul.
Article in English | MEDLINE | ID: mdl-27212634

ABSTRACT

Surgical aortic valve replacement may be complicated by severe dynamic left ventricular outflow tract obstruction and cardiogenic shock in the postoperative period. We present a patient who developed severe anterior motion following aortic valve and Cox MAZE surgery which necessitated a mitral valve replacement. doi: 10.1111/jocs.12763 (J Card Surg 2016;31:429-431).


Subject(s)
Aortic Valve Stenosis/surgery , Aortic Valve/surgery , Cardiac Surgical Procedures/methods , Heart Valve Prosthesis Implantation/methods , Mitral Valve/surgery , Postoperative Complications/diagnostic imaging , Ventricular Outflow Obstruction/diagnostic imaging , Aged , Aortic Valve Stenosis/complications , Atrial Fibrillation/complications , Atrial Fibrillation/surgery , Echocardiography , Humans , Male , Severity of Illness Index , Shock, Cardiogenic/diagnostic imaging
16.
Ned Tijdschr Geneeskd ; 154: A1302, 2010.
Article in Dutch | MEDLINE | ID: mdl-20977791

ABSTRACT

Local anaesthetics are routinely used for several indications, but despite local administration their use may lead to systemic toxicity. The symptoms include numbness of the tongue, dizziness, tinnitus, visual disturbances, muscle spasms, convulsions, coma, and respiratory and cardiac arrest. Recently, an intravenous lipid emulsion was reported to act as a novel potential antidote for systemic toxicity due to local anaesthetics. We describe the application of this lipid emulsion in a 27-year-old patient with generalized seizures and coma due to local anaesthetic toxicity. She recovered quickly and was responsive again 10 minutes after the intravenous administration of the lipid emulsion.


Subject(s)
Anesthetics, Local/antagonists & inhibitors , Anesthetics, Local/toxicity , Coma/chemically induced , Fat Emulsions, Intravenous/therapeutic use , Seizures/chemically induced , Adult , Coma/drug therapy , Female , Humans , Seizures/drug therapy , Treatment Outcome
17.
J Am Chem Soc ; 132(14): 5236-40, 2010 Apr 14.
Article in English | MEDLINE | ID: mdl-20232863

ABSTRACT

Adenosine diphosphate ribosylation (ADP-ribosylation) is a widely occurring post-translational modification of proteins at nucleophilic side chains of amino acid residues, such as asparagine, glutamic acid, and arginine. Elucidation of the biological role of ADP-ribosylation events would benefit from the availability of well-defined ADP-ribosylated peptides. Main issues in the construction of synthetic ADP-ribosylated peptides involve the availability of protected ribosylated amino acids suitable for peptide synthesis, development of a protective group strategy for peptide fragments compatible with the integrity of the adenosine diphosphate moiety, and an efficient procedure for pyrophosphate formation. In this paper we present a first approach to the chemical synthesis of ADP-ribosylated peptides in solution and on solid support. We describe an efficient synthesis of suitably protected ribosylated asparagine and glutamine building blocks suitable for Fmoc-based peptide synthesis. We further demonstrate a successful application of these ribosylated amino acids in the assembly of three fully synthetic ADP-ribosylated peptides by solution and solid phase approaches.


Subject(s)
Adenosine Diphosphate Ribose/chemical synthesis , Asparagine/chemistry , Glutamine/chemistry , Oligopeptides/chemical synthesis , Adenosine Diphosphate Ribose/chemistry , Molecular Structure , Oligopeptides/chemistry , Stereoisomerism
18.
Org Lett ; 10(20): 4461-4, 2008 Oct 16.
Article in English | MEDLINE | ID: mdl-18800840

ABSTRACT

A one-pot procedure for the preparation of phosphoramidates, phosphorothioates, pyrophosphates, phosphodiesters, and phosphofluoridates has been devised using di(p-methoxybenzyl)-N,N-diisopropylphosphoramidite as the common phosphitylating reagent.


Subject(s)
Diphosphates/chemistry , Esters/chemical synthesis , Organophosphorus Compounds/chemistry , Esters/chemistry , Molecular Structure
19.
J Gene Med ; 9(12): 1071-9, 2007 Dec.
Article in English | MEDLINE | ID: mdl-17902184

ABSTRACT

Glial fibrillary acidic protein (GFAP) is an intermediate filament protein abundantly expressed in malignant gliomas. We have constructed a novel oncolytic adenovirus, Ad5-gfa2(B)3-E1, for treatment of these tumors. In this construct, the E1 region is under control of the tissue-specific GFAP promoter (gfa2) with three additional copies of the glial specific 'B' enhancer. Infection of a GFAP-positive cell line with Ad5-gfa2(B)3-E1 resulted in E1A and E1B expression at 75% and 30% of the levels obtained after wtAd5 infection. Q-PCR showed that Ad5-gfa2(B)3-E1 replicated 4.5 times more efficiently in the GFAP-positive than in the GFAP-negative cell lines. Cell viability assays showed efficient elimination of GFAP-positive cells by Ad5-gfa2(B)3-E1, in some cell lines as efficiently as wtAd5, while the elimination was attenuated in GFAP-negative cell lines. When tested in human tumor xenografts in nude mice, Ad5-gfa2(B)3-E1 effectively suppressed the growth of GFAP-positive SNB-19 glial tumors but not of GFAP-negative A549 lung tumors. In Ad5-gfa2(B)3-E1, the E3 region was deleted to create space for future insertion of heterologous therapeutic genes. Experiments with dl7001, an E3-deleted variant of wtAd5, confirmed that the specificity of Ad5-gfa2(B)3-E1 replication was based on the promoter driving E1 and not on the E3 deletion. Strategies to further improve the efficacy of Ad5-gfa2(B)3-E1 for the treatment of malignant gliomas include the insertion of therapeutic genes in E3 or retargeting to receptors that are more abundantly expressed on primary glioma cells than CAR.


Subject(s)
Adenoviridae/genetics , Brain Neoplasms/therapy , Glial Fibrillary Acidic Protein/antagonists & inhibitors , Glioma/therapy , Adenoviridae/physiology , Brain Neoplasms/pathology , Glioma/pathology , Humans , Polymerase Chain Reaction , Virus Replication
20.
J Nucl Med ; 47(9): 1483-9, 2006 Sep.
Article in English | MEDLINE | ID: mdl-16954557

ABSTRACT

UNLABELLED: The overall median survival of patients with a malignant glioma is <1 y. Because malignant gliomas rarely metastasize outside the skull, locoregional treatment strategies, such as gene therapy, are under investigation. Recently, convection-enhanced delivery (CED) has been presented as a method to improve delivery of large molecules. The goal of this study was to evaluate whether CED improves intratumoral delivery of adenoviral vectors and compare it with single injection (SI) and multiple injection (4x, MI). METHODS: A replication-deficient adenoviral vector encoding the herpes simplex virus thymidine kinase (HSV-tk) and the human somatostatin receptor subtype 2 (sst(2)) was administered into nude mice bearing subcutaneous U87 xenografts. Tumors were injected with 1.5 x 10(9) plaque-forming units of Ad5.tk.sstr by CED, SI, or MI. Three days later, [(99m)Tc-N(4)(0-1),Asp(0),Tyr(3)]octreotate ((99m)Tc-Demotate 2) was injected intravenously to monitor the virus-induced sst(2) expression. gamma-Camera imaging was performed for in vivo imaging, and the tumor uptake of (99m)Tc-Demotate 2 was determined by gamma-counter. Furthermore, the tumor was sectioned and ex vivo autoradiography was performed. After decay of radioactivity, adjacent sections were submitted to in vitro autoradiography with (125)I-DOTA-Tyr(3)-octreotate, which was used to calculate the transduced areas. RESULTS: Transfected xenograft tissues showed high sst(2) expression and were clearly visualized with a gamma-camera. Accumulation of radioactivity was 2-fold higher in the tumors that were injected with MI compared with CED and SI (P = 0.01). CED and SI resulted in equal uptake of radioactivity in the tumors. The measured areas of transduction in ex vivo and in vitro autoradiographs showed a high concordance (r(2) = 0.89, P < 0.0001). The maximum area of transfection was significantly larger after MI than after CED (P < 0.05) or SI (P = 0.05). Also, the measured volume of distribution was twice as high after administration of Ad5.tk.sstr by MI (56.6 mm(3)) compared with SI (25.3 mm(3)) or CED (26.4 mm(3)). CONCLUSION: CED does not increase adenoviral vector distribution in a glioma xenograft model compared with SI. Therefore, in the clinic MI is probably the most effective delivery method for the large adenoviral particle (70 nm) in malignant gliomas.


Subject(s)
Adenoviridae/genetics , Catheterization/methods , Genetic Vectors/genetics , Glioblastoma/genetics , Glioblastoma/virology , Infusions, Intralesional/methods , Transfection/methods , Animals , Cell Line, Tumor , Humans , Male , Mice , Mice, Nude
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